Alzheimer's disease is a neurodegenerative brain disorder and a common causes of dementia in the elderly that affected over 5.4 million people in the United States of America in 2013. Since its first description by Alois Alzheimer in 1907 this disease has been thought to result from pathological features in the brain called plaques and tangles. For over one hundred years all clinical efforts to stop or prevent the progression of Alzheimer's disease have failed and new perspectives into the cause(s) of this disorder are lacking. This invention provides a therapeutic approach to treating Alzheimer's disease that emerged from the inventor's understanding that plaques and tangles causative but mere consequences of an underlying mechanism in which the clearance of toxic factors from the brain has been disrupted by genetic and/or environmental factors. A detailed discussion of this reasoning was published after the provisional patent application date and is provided with this application (Ethell, D W; Disruption of cerebrospinal fluid flow through the olfactory system may contribute to Alzheimer's disease pathogenesis, Journal of Alzheimers Disease 451(4):1021-30, 2014). Characteristic accumulation of amyloid-beta (Aβ) deposits in early Alzheimer's disease indicate the underlying mechanism involves a disruption of interstitial fluid/cerebrospinal fluid (CSF) flow that normally clears debris and toxins from extracellular spaces within the brain. The earliest pathological features of Alzheimer's disease occur in brain areas near the primary olfactory cortex of the brain. During homeostasis, CSF flows from the medial temporal lobe (MTL) along the lateral olfactory stria, through the olfactory trigone and down the olfactory tract to the olfactory bulb, where it seeps through the cribriform plate and into the nasal submucosa. Lymphatic vessels within the nasal submucosa carry off the CSF and metabolites carried therein. The significance of this CSF flow for neurological disease has not been appreciated until this invention, and it is shown here that this pattern of CSF flow clears metabolites, debris and toxins from the hippocampal formation, entorhinal cortex and other structures in the medial temporal lobe, as well as the basal forebrain. Disruption of CSF flow along this route facilitates the accumulation of Aβ in the medial temporal lobe, basal forebrain, and nearby areas, predisposing them to accumulate and trigger the formation of pathological features such as plaques and tangles.
Factors that reduce CSF drainage across the cribriform plate slow the clearance of CSF from the medial temporal lobe and basal forebrain, which can include aging-related bone changes, head trauma, inflammation of the nasal epithelium, toxins that affect olfactory neuron survival and renewal, as well as vascular effects related to diabetes, obesity, and atherosclerosis—all of which have been proposed to affect AD risk; reductions in CSF-mediated clearance also provide links between those life events and familial mutations linked with early onset Alzheimer's disease, in PSEN1, PSEN2, and APP.
Disruption of CSF flow across the cribriform plate predisposes the medial temporal lobe and basal forebrain to pathology, so the intervention attenuates the development of brain pathology by increasing the drainage of CSF from the area overlying the cribriform plate. The invention reduces risks and complications associated with Alzheimer's disease as well as other neurological and psychiatric conditions, e.g., Parkinson's disease, frontal-temporal dementia, mild cognitive impairment, idiopathic dementia, vascular dementia, amyotrophic lateral sclerosis, Pick's disease, concussive brain injury, supranuclear palsy, Creutzfeld-Jacob disease, normal pressure hydrocephalus, multiple sclerosis.